nraveling tumor response and resistance to combined chemotherapy and PD-L1 inhibition with minimal invasive techniques in patients with advanced NSCLC with targetable disease
- Conditions
- Lung CancerNon-small cell lung cancer10027656
- Registration Number
- NL-OMON54889
- Lead Sponsor
- niversitair Medisch Centrum Groningen
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Recruiting
- Sex
- Not specified
- Target Recruitment
- 100
1. Provision of signed and dated, written informed consent.
2. Female and male subjects aged at least 18 years.
3. Subjects with histologically- or cytologically-documented non squamous NSCLC
with a documented driver mutation (such as EGFR, ALK, ROS, BRAF, MET, RET,
NTRK1-3, KRAS, NRG1, HER 2).
4. New (< 3 month old) tumor specimen (histology or cytology containing enough
tumor cells and tumor DNA for at least NGS and PD-L1 staining confirmed by a
pathologist). If the tumor specimen reveals a possible new targetable driver
than that has to be discussed with the subject as an option next to this study.
5. Locally advanced or metastatic NSCLC, not amenable to curative surgery or
radiotherapy.
6. Evidence of radiological disease progression following first line TKI or any
subsequent treatment lines with TKI only (for EGFR treated with either
osimertinib or failure of other TKIs 2nd line or later). Previous course of
chemotherapy is allowed, but not necessary as well.
7. ECOG performance status 0-1 with no deterioration over the previous 2 weeks
and a minimum life expectancy of 12 weeks.
8. At least one lesion, not previously irradiated and not chosen for biopsy
during the study screening period, that can be accurately measured at baseline
as >= 10mm in the longest diameter (except for pathological lymph nodes they
must be >= 15mm in short axis) with computerized tomography (CT) or magnetic
resonance imaging (MRI) which is suitable for accurate repeated measurements.
9. Adequate hematologic and end organ function, defined by the following
laboratory results obtained within <=14 days prior to study treatment:
o ANC >=1500 cells/µL (without granulocyte colony-stimulating factor support)
o WBC counts >2500/µL
o Lymphocyte count >=500/µL
o Platelet count >=100,000/µL (without transfusion)
o Hemoglobin >=9.0 g/dL. Patients may be transfused or receive erythropoietic
treatment to meet this criterion.
o AST, ALT, and alkaline phosphatase <= 2.5× the upper limit of normal (ULN),
with the following exceptions:
- Patients with documented liver metastases: AST and/or ALT <= 5 × ULN
- Patients with documented liver or bone metastases: alkaline phosphatase <= 5 ×
ULN
o Serum bilirubin <= 1.5 × ULN. Patients with known Gilbert disease who have
serum bilirubin level <= 3 × ULN may be enrolled.
o INR and aPTT <= 1.5 × ULN. This applies only to patients who are not receiving
therapeutic anticoagulation; patients receiving therapeutic anticoagulation
should be on a stable dose.
o Creatinine clearance >= 30 mL/min.
10. Females should be using adequate contraceptive measures, should not be
breast feeding and must have a negative pregnancy test prior to start of dosing
if of child-bearing potential or must have evidence of non-child-bearing
potential by fulfilling one of the following criteria at screening:
o Post-menopausal defined as aged more than 50 years and amenorrhoeic for at
least 12 months following cessation of all exogenous hormonal treatments.
o Women under 50 years old would be considered postmenopausal if they have been
amenorrhoeic for 12 months or more following cessation of exogenous hormonal
treatments and with Luteinizing Hormone (LH) and Follicle-Stimulating Hormone
(FSH) levels in the post-menopausal range for the institution.
o Documentation of irreversible s
1. Treatment with any other investigational agent or participation in another
clinical trial with therapeutic intent within 14 days prior to inclusion of the
study.
2. Prior treatment with CD137 agonists or immune checkpoint blockade therapies,
anti*PD-1, and anti*PD-L1 therapeutic antibodies.
• Patients who have had prior anti*CTLA-4 treatment may be enrolled, provided
the following requirements are met:
o Minimum of 6 weeks from the last dose of anti*CTLA-4
o No history of severe immune related adverse effects from anti*CTLA-4 (CTCAE
Grade 3 and 4).
3. CNS disease, treated brain metastases without the need for steroids are
allowed.
4. Leptomeningeal disease.
5. Uncontrolled tumor-related pain.
• Patients requiring pain medication must be on a stable regimen at study entry.
• Symptomatic lesions amenable to palliative radiotherapy (e.g., bone
metastases or metastases causing nerve impingement) should be treated prior to
enrollment. Patients should be recovered from the effects of radiation. There
is no required minimum recovery period.
• Asymptomatic metastatic lesions whose further growth would likely cause
functional deficits or intractable pain (e.g., epidural metastasis that is not
currently associated with spinal cord compression) should be considered for
loco-regional therapy if appropriate prior to enrollment.
6. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring
recurrent drainage procedures (once monthly or more frequently).
7. Malignancies other than NSCLC within 3 years prior with the exception of
those with a negligible risk of metastasis or death treated with expected
curative outcome (such as adequately treated carcinoma in situ of the cervix,
basal or squamous cell skin cancer, localized prostate cancer treated with
curative intent, ductal carcinoma in situ treated surgically with curative
intent).
8. Pregnant and lactating women.
9. History of severe allergic, anaphylactic, or other hypersensitivity
reactions to chimeric or humanized antibodies or fusion proteins.
10. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese
hamster ovary cell products or any component of the atezolizumab formulation.
11. History of autoimmune disease, including but not limited to myasthenia
gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus,
rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis
associated with antiphospholipid syndrome, Wegener*s granulomatosis, Sjögren*s
syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or
glomerulonephritis.
• Patients with a history of autoimmune-related hypothyroidism on a stable dose
of thyroid replacement hormone may be eligible for this study.
• Patients with controlled Type I diabetes mellitus on a stable dose of insulin
regimen may be eligible for this study.
12. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g.,
bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or
evidence of active pneumonitis on screening chest CT scan.
• History of radiation pneumonitis in the radiation field (fibrosis) is
permitted.
13. Positive test for HIV.
14. Patients with active hepatitis B (chronic or acute; defined as having a
positive hepatitis B surface antigen [HBsAg] test at screening)
Study & Design
- Study Type
- Observational non invasive
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>Primary Endpoint:<br /><br>Response to treatment defined as Progression Free Survival (PFS) in months<br /><br>according to RECIST v1.1 and divided into the following subgroups of response:<br /><br>- primary resistance (PFS < 6 mo);<br /><br>- acquired resistance (PFS >= 6 mo).<br /><br>Primary predictor variable:<br /><br>The change in level of ctDNA measured by ddPCR in blood between week 12 (end of<br /><br>chemotherapy) and week 18.</p><br>
- Secondary Outcome Measures
Name Time Method <p>Secondary endpoints:<br /><br>1. Overall survival<br /><br>2. Time to biological progression, defined as an increase of >= 30% in the<br /><br>levels of the specific mutation from the lowest value achieved, measured in<br /><br>ctDNA in blood using ddPCR.<br /><br>3. Immune related adverse events (irAE).<br /><br>4. Quality of life and symptom scores.</p><br>